Although there have been great improvements in the diagnosis and treatment of cancer, many people die from cancer each year, and their deaths are typically due to metastases and cancers that are resistant to conventional therapies.
Most drug-mediated cancer therapies rely on chemotherapeutical agents, i.e. cytotoxic agents, selective for dividing cells. These agents are usually administered at or near maximum tolerated doses resulting in frequent dramatic toxicities that compromise the quality of life and have a severe effect on the immune response. However, such drugs almost inevitably do not kill all of the cancer cells in the patient since some of them acquire a resistance against the particular drug.
Anticancer drugs in general are more effective when used in combination. In particular, combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s). The major advantages of combining chemotherapeutic drugs are that it may promote additive or possible synergistic effects through biochemical interactions and may also decrease the emergence of resistance in early tumor cells which would have been otherwise responsive to initial chemotherapy with a single agent. An example of the use of biochemical interactions in selecting drug combinations is demonstrated by the administration of leucovorin to increase the binding of an active intracellular metabolite of 5-fluorouracil to its target, thymidylate synthase, thus increasing its cytotoxic effects.
Various combination and treatment schemes were developed to overcome the developing drug resistance of cancer cells so that nowadays numerous combinations, mainly of conventional cytotoxic drugs, are used in current treatments. An extensive review of current medical practices may be found in “Oncologic Therapies” edited by E. E., Vokes and H. M. Golomb, published by Springer.
Kinase Inhibitors in Combination with Chemotherapeutics of Other Classes
Several references describe combinations of Sunitinib malate with other agents. For example, U.S. Patent Publication No. 2003-0216410 describes combinations of sunitinib malate with cyclooxygenase inhibitors. U.S. Patent Publication No. 2004-0152759 describes combinations of sunitinib malate with several agents, such as CPT-11 (topoisomerase inhibitor irinotecan, Camptosar™), the cytosceletal disruptor docetaxel and 5-fluorouracil (5-FU). However, no combinations with active immunotherapy are disclosed.
Kinase Inhibitors in Combination with Non-Specific Immunotherapy
Non-specific immunotherapy usually relies on molecule such as cytokines and interleukins to activate the immune system of a recipient in a non-specific manner so that an already present but weak immune response of the patient may be enhanced to reach beneficial levels. The rational behind this kind of treatment is the fact that tumor cells usually do not express MHC II and costimulators, which means that they usually do not activate helper T cells and no immune response ensues. Cytokine/interleukin treatment attempts to by-pass the need for helper T cells by providing cytokines for T cell growth and activation. Trials currently are under way to determine whether a combination of the TKI Genistein with interleukin-2 may be beneficial (Phase II Pilot Study of Genistein and High-Dose Interleukin-2 in Patients With Metastatic Malignant Melanoma or Renal Clear Cell Carcinoma NCT00276835).
While chemotherapeutics and their combinations are the mainstay of the majority of antitumor drug treatment strategies, other classes of drugs are being developed. They include specific active and passive immunotherapies. Additional combination therapies and treatment regimens encompassing these novel specific immunotherapies for the treatment of neoplastic cell growth, such as cancers are being developed.
Antigen-Specific Vaccination in Combination with Non-Specific Immunotherapy
Cytokines generally stimulate proliferation or differentiation of cells of the hematopoietic lineage or participate in the immune and inflammatory response mechanisms of the body. The interleukins are a family of cytokines that mediate immunological responses. Central to an immune response is the T cell, which produces many cytokines and plays a role in adaptive immunity to antigens. Cytokines produced by the T cell have been classified as type 1 and type 2 (Kelso, A. Immun. Cell Biol. 76:300-317, 1998). Type 1 cytokines include IL-2, IFN-γ, LT-α, and are involved in inflammatory responses, viral immunity, intracellular parasite immunity and allograft rejection. Type 2 cytokines include IL4, IL-5, IL-6, IL-10 and IL-13, and are involved in humoral responses, helminth immunity and allergic response. Shared cytokines between Type 1 and 2 include IL-3, GM-CSF and TNF-α. There is some evidence to suggest that Type 1 and Type 2 producing T cell populations preferentially migrate into different types of inflamed tissue. Cytokines such as GM-CSF are often used in lower doses as adjuvants in vaccination therapy.
Vaccination with tumor cells genetically engineered to produce interleukin (IL)-2 provides another strategy to enhance antitumor immune responses (Koppenhagen F J et al., Clin Cancer Res. 1998 (8):1881-1886).
Conventional Chemotherapeutics in Combination with Active Immunotherapy
Machiels et al. observed that cyclophosphamide, paclitaxel, and doxorubicin, when given in a defined sequence either before or after the whole-cell vaccine and by a different route of administration with a GM-CSF-secreting, neu-expressing whole-cell vaccine, enhanced the vaccine's potential to delay tumor growth in neu transgenic mice. In addition, it was shown that these drugs mediate their effects by enhancing the efficacy of the vaccine rather than via a direct cytolytic effect on cancer cells. Furthermore, paclitaxel and cyclophosphamide appear to amplify the T helper 1 neu-specific T-cell response. These findings suggest that the combined treatment with immune-modulating doses of DNA interfering chemotherapy and the GM-CSF-secreting neu vaccine can overcome immune tolerance and induce an antigen-specific antitumor immune response (Machiels et al. Cancer Res 2001 May 1; 61(9):3689-97).
Another study (C J Wheeler et al, Clin Cancer Res, 2004, Aug. 15, Clinical Responsiveness of Glioblastoma Multiforme to Chemotherapy after Vaccination) suggested that chemotherapy synergizes with previous therapeutic vaccination to generate a uniquely effective treatment that slows Globlastoma Multiforme (GBM) progression and significantly extends patient survival relative to individual therapies. Tumors treated with dendritic cell therapy were highly sensitive to subsequent chemotherapy suggesting that the vaccine either primes' the cell-death machinery or fundamentally alters the genetic or structural makeup of the tumor cells.
US2006-051354 suggests the use immunomodulator chemotherapeutic agents as adjuvants for vaccines. The inventors found that paclitaxel triggers the induction of MCP-1, a chemokine known to recruit dendritic cells (APC) at the injection site, a critical event for the induction of immune responses and therefore proposed to enhance immunogenicity of a vaccine by combining directly low-dose immunomodulator chemotherapeutic agents with the vaccine in one single administration. However, no combination treatment with therapeutical anti-neoplastic doses of a chemotherapeutic was disclosed.
Virtually all chemotherapeutics, including kinase inhibitors cause depression of the immune system when used in therapeutical doses, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells and platelets. Depending on their target, some monoclonal antibodies used in cancer therapy also have a detrimental effect on the immune system.
Thus, it was surprising to find, that small molecules, kinase inhibitors and antibodies that lead to a suppressed immune system do not prevent the desired immune response when used in combination with active immunotherapy.